Non-collagenous proteins vs. bone fragility

描述(申请人提供)：骨脆性骨折是我们快速老龄化社会的一个主要医疗保健问题，因为它增加了长期残疾甚至过早死亡的风险，并且总是与骨骼的超微结构变化有关。在骨的层次结构中，片层是由矿化的胶原纤维组成的片状生物复合材料，由矿物晶体和非胶原蛋白(NCPs)组成的纤维外基质，以及填充在间质中的水，是人类骨骼的基本构建单位。尽管矿化胶原纤维的力学行为已经得到了广泛的研究，但纤维外基质对骨的力学行为的贡献仍然知之甚少。以往的证据表明，NCPs不仅可以调节骨代谢，而且对骨的超微结构完整性也有重要的作用。在这项研究中，我们提出了一个机制模型 骨骼中的纤维外基质，基质中的矿物晶体通过NCP的薄有机界面结合在一起。总的假设是，非胶原蛋白(NCPs)通过促进骨纤维外基质中HA多晶之间的界面滑动，在骨纳米力学中发挥关键作用。为了验证这一假设，将进行数值模拟和实验验证，以解决这两个具体目标。目的1：采用一种新的界面区模型，用有限元方法确定羟基磷灰石(HA)多晶之间的有机界面对骨中纤维外基质力学行为的影响：在目标1中，一种新的界面区模型将用于纤维外基质的有限元模拟，其中羟基磷灰石(HA)多晶体通过由NCPs和水分子组成的有机界面结合在一起，允许矿物晶体之间的滑动和分离。预计塑性变形 是通过HA晶体之间沿有机界面的滑动来实现的。此外，本研究还将详细研究晶体大小、形状和取向分布对纤维外基质力学行为的影响。目的2利用体外实验模型对新的机制模型进行实验验证：在目标2中，我们假设如果通过去除多糖来改变蛋白多糖的结构，将损害纤维外基质中矿物晶体之间的有机界面，多糖是帮助GAG锚定在核心蛋白上的蛋白多糖的主要成分。PGs的中断将导致矿物晶体之间的界面带缺陷，从而导致片层的弱化。为了验证这一假设，我们建议使用一种新的纳米缝隙测试技术[81]来测量在有和没有蛋白多糖损伤的情况下单个薄板的原位机械性能。这项研究中提出的新的机制模型如果得到证实，将为研究NCPs在骨脆性中的结构作用开辟一条新的途径。这种理解的潜在影响是多方面的。首先，它将显著地 完善骨组织多尺度建模。其次，这一概念可以扩展到阐明NCPs在年龄和疾病相关的骨脆性骨折中的作用。最后，NCP可在临床环境中用作评估骨脆性骨折风险的生物标记物。

DESCRIPTION (provided by applicant): Bone fragility fracture is a major health care concern for our rapidly aging society due to its elevated risk of long-term disability and even premature death and is always associated with ultrastructural changes in bone. In the hierarchy of bone, lamellae, as the basic building unit of human bone, are a sheet-like biocomposite consisting of mineralized collagen fibrils, an extrafibrillar matrix comprised of mineral crystals and non-collagenous proteins (NCPs), and water filling the interstitial spaces. Although the mechanical behavior of mineralized collagen fibrils have been extensively studied, the contribution of the extrafibrillar matrix to the mechanical behavior of bone is still poorly understood. Previous evidence shows that NCPs may not only regulate bone metabolisms but also play a significant role in the ultrastructural integrity of bone. In this study, we propose a mechanistic model of the extrafibrillar matrix in bone that the mineral crystals in the matrix are bounded through a thin organic interface of NCPs. The overall hypothesis is that non-collagenous proteins (NCPs) play a critical role in bone nanomechanics by facilitating the interfacial sliding between the HA polycrystals in the extrafibrillar matrix of bone. To test the hypothesis, both numerical simulations and experimental verifications will be implemented to address the two specific aims. Aim 1: To determine the effect of the organic interface between HA polycrystals on the mechanical behavior of the extrafibrillar matrix in bone using a finite element approach with a novel interface zone model: In Aim 1, a novel interface zone model will be used in the finite element simulation of the extrafibrillar, in which hydroxyapatite (HA) polycrystals are bounded through an organic interface, which is comprised of NCPs and water molecules and allows for sliding and separation between the mineral crystals. It is anticipated that the plastic deformation is realized through the sliding between HA crystals along the organic interface. In addition, the effect of crystal size and shape and orientation distribution on the mechanical behavior of the extrafibrillar matrix will be scrutinized in this study. Aim 2 To experimentally verify the novel mechanistic model using an in vitro experimental model: In Aim 2, we hypothesize that the organic interface between the mineral crystals in the extrafibrillar matrix will be compromised if the structure of proteoglycans is altered by removing polysaccharides, which are the major components of proteoglycans that help anchor the GAGs onto the core proteins. The interruption of PGs will result in a defected interface zone between the mineral crystals, thus leading to weakening of the lamellae. To test the hypothesis, we propose to use a novel nanoscratch test technique [81] to measure the in situ mechanical properties of individual lamellae with and without impairment of proteoglycans. The novel mechanistic model proposed in this study, if proved, will open a new avenue for studying the structural role of NCPs in bone fragility. The potential impact of such understanding is multifaceted. First, it will significantly improve the multiscale modeling of bone tissues. Second, this concept can be extended to elucidate the involvement of NCPs in age- and disease related bone fragility fractures. Finally, NCPs may be used as biomarkers in clinical settings to assess the risk of bone fragility fractures.